Reactive Intravascular B-Cell Immunoblastic Proliferation: A Recently Described Entity and a Mimicker of Intravascular Lymphoma

Abstract

Reactive intralymphovascular immunoblastic proliferation (ILVIP) is a rare and diagnostically challenging entity that can closely mimic intravascular large B-cell lymphoma (IVLBCL). We report the comprehensive clinicopathologic features of two patients with B-cell lineage ILVIP identified in bowel resection specimens. Both patients presented with small bowel obstruction requiring surgical intervention, and one patient was initially erroneously diagnosed with IVLBCL. Neither patient had systemic findings suggestive of lymphoma, such as lymphadenopathy, hepatosplenomegaly, or B symptoms. Histologic evaluation demonstrated focal ILVIP composed of intermediate-to-large B-lineage immunoblasts positive for CD45, CD79a, and MUM1 with polytypic light-chain expression, and negative for CD20, PAX5, CD138, Epstein–Barr virus, and HHV8. The immunoblasts showed a high proliferation index (80–100%) in both cases. Recognition of ILVIP in specimens resected for bowel obstruction in otherwise healthy patients is essential to avoid misinterpretation as intravascular lymphoma and prevent unnecessary treatment.

1. Introduction

Immunoblasts are activated mature B- or T-cell lineage lymphocytes characterized by intermediate-to-large cell size, enlarged nuclei with vesicular chromatin, prominent nucleoli, and variably abundant cytoplasm. During B-cell activation, immunoblasts commonly downregulate CD20 and may acquire CD30 expression, particularly secondary to infections or inflammation [1,2,3].

Reactive ILVIP is an uncommon finding in gastrointestinal specimens from patients with both acute and chronic inflammatory conditions, characterized by proliferation of immunoblasts within lymphovascular spaces [4]. B-cell lineage immunoblastic proliferations have been also described in lymph node sinuses [5]. Isolated reports have linked intralymphovascular immunoblastic proliferations to gastric mucosa-associated lymphoid tissue (MALT) lymphoma [6], as well as atypical CD30-positive T-cell immunoblastic proliferations identified in conjunction with lichen sclerosis and an endometrial polyp [7,8,9]. B-cell lineage ILVIP shows polytypic light chain expression and lacks immunoglobulin gene rearrangement, supporting a reactive nature. However, rare cases with T-cell immunoblastic proliferations have shown immunoglobulin gene rearrangement, a finding of uncertain clinical significance [9]. Although considered reactive, ILVIP can morphologically mimic intravascular lymphoma, posing a significant diagnostic pitfall with critical therapeutic implications.

In this study, we describe clinicopathologic features of reactive B-cell ILVIP incidentally identified in two patients who presented with small bowel obstruction requiring right hemicolectomy (patient 1) or small bowel resection (patient 2). However, patient #2 was erroneously diagnosed with intravascular large B-cell lymphoma and referred to our institution for further evaluation, highlighting the diagnostic challenge posed by ILVIP and the potential consequences of misinterpretation, including unwarranted workup, undue patient anxiety, and possible overtreatment.

2. Case Reports

Patient 1, a 71-year-old female, presented with abdominal pain following planned perineal hernia repair. Laboratory evaluation showed a white blood cell count of 7.9 K/µL with relative neutrophilia (86%). There was no lymphadenopathy, hepatosplenomegaly, fever, or night sweats. Abdominal imaging demonstrated small bowel obstruction with colonic ischemia requiring ileocolonic resection.

Histologic evaluation of the resected colon revealed perforated ischemic colitis with serosal adhesions. Additionally, a focal intralymphovascular proliferation of atypical lymphoid cells was observed. These cells were intermediate to large in size, with round to slightly irregular nuclei, vesicular chromatin, variably prominent nucleoli, and frequent apoptotic bodies (Figure 1A,

Table 1. Clinicopathologic features of two patients with intralymphovascular immunoblastic proliferation (ILVIP).

Patient No.	Age/ Sex	Clinical Presentation	Imaging	Procedure	Immunophenotype	Follow-Up
1	71/ F	SBO after perineal hernia repair; no B-symptoms; no hepatosplenomegaly	partial SBO	Right hemicolectomy	Positive: CD19, CD45, CD79a, MUM1; polytypic light chains	Died due to sepsis
					Negative: CD3, CD10, CD20, CD30, PAX5, CD138, ALK1, EBV-, HHV8-
					High proliferative index (MIB1 100%)
2	85/ F	SBO due to incarcerated ventral hernia; no B-symptoms; no hepatosplenomegaly	ventral hernia with SBO	Partial small bowel resection	Positive: small subset CD3, CD38, CD45, CD79a, MUM1, weak CD30; polytypic light chains	Healthy
					Negative: CD10, CD20, PAX5, CD138, ALK1, EBV, HHV8
					High proliferative index (Ki67 80%)

SBO—small bowel obstruction

). Immunohistochemical studies confirmed B-cell lineage, with strong expression of CD45, CD19, CD79a, and MUM1 with polytypic kappa and lambda light chain expression. The cells were negative for CD3, CD20, CD30, CD138, CD10, ALK1, and TDT. HHV8 and EBV (by in-situ hybridization) were negative. The proliferation index was high (100% by MIB1). The endothelial cells were positive for CD31 and D2-40, suggestive of a lymphatic vessel. PCR-based clonality testing performed on the section of colon with immunoblastic proliferation demonstrated no clonal IGH or IGK gene rearrangements. Flow cytometry was not performed. Unfortunately, despite treatment with antibiotic therapy, the patient died several weeks later from sepsis-related complications.

Patient 2, an 85-year-old female, presented with a small bowel obstruction secondary to an incarcerated ventral hernia. Laboratory evaluation showed mild leukocytosis (white blood cell count 11.5 k/μL) with absolute neutrophilia. There was no lymphadenopathy, hepatosplenomegaly, fever, chills, weight loss, or night sweats. The patient underwent surgical repair with small bowel resection.

Histologic evaluation of the small bowel demonstrated a focal intravascular proliferation of atypical lymphoid cells. The cells were intermediate to large in size, with enlarged irregular nuclei, variably prominent nucleoli, and abundant apoptotic debris. Immunohistochemical studies supported B-cell lineage with expression of CD45, CD79a, CD38, MUM1, and polytypic immunoglobulin kappa and lambda light chains (confirmed by immunohistochemistry and in situ hybridization). A minor subset of cells showed CD3 and weak CD30 expression. The cells lacked expression of CD20, PAX5, CD10, BCL-6, CD138, Cyclin D1, Sox11, C-MYC, TdT, CD34, and ALK1. EBV and HHV8 were negative. Ki67 showed a high proliferative index (80%) (Figure 1B, Table 1). The vascular lining was not apparently positive for D2-40 and CD34, not conclusive for lymphatic or blood vessel origin. Flow cytometry and PCR clonality testing were not performed on the lesional tissue.

The patient was initially diagnosed with IVLBCL at the referring institution and underwent PET/CT, bone marrow biopsy, and brain/spine MRI, all of which showed no evidence of lymphoma. Review at our institution supported a diagnosis of reactive ILVIP. The patient was observed without systemic therapy and remains healthy.

3. Discussion

ILVIP is a rare, reactive intralymphovascular proliferation of intermediate-to-large immunoblasts most commonly identified in gastrointestinal specimens from patients with acute inflammation, infection, or mechanical obstruction without evidence of lymphoma [4]. These immunoblasts most often exhibit B-cell lineage with postgerminal center immunophenotype. However, less common T-cell immunoblastic variants have also been described [7,8,9]. The morphologic and immunophenotypic features of ILVIP may closely overlap with intravascular lymphoma or leukemia, with IVLBCL most concerning in immunoblasts with B-cell immunophenotype. Distinguishing ILVIP from IVLBCL is critical, as the latter is an aggressive malignancy requiring intensive chemotherapy and is associated with a poor prognosis, with a five-year overall survival rate of approximately 50% [10].

To date, the two largest series of ILVIP describe eight cases of B-cell lineage immunoblastic proliferation in gastrointestinal resection specimens and twelve cases involving lymph node sinuses [4,5]. Our two cases share a similar clinical presentation that parallels prior observations that ILVIP occurs most often in gastrointestinal specimens associated with infection, inflammation, or mechanical obstruction, suggesting that they represent a localized reactive response [4]. The mechanism underlying intralymphovascular accumulation of immunoblasts remains incompletely understood, although alterations in adhesion molecule expression (LFA-1, ICAM-1) or intestinal lymphatic obstruction have been proposed to play a role [11].

In both our cases, ILVIP was identified as a focal finding. The immunoblasts exhibited a post-germinal center B-cell immunophenotype, characterized by the expression of CD45, CD79a, and MUM1, and the absence of CD10, CD138, CD20, and PAX5. Immunoglobulin light chain expression was polytypic in both cases, and B-cell clonality by PCR was negative for immunoglobulin rearrangement in patient 1. Unlike previously reported series, our cases lacked significant CD30 expression and were negative for definitive PAX5 and CD20 expression [4]. A small subset of CD3-positive immunoblasts was present in Patient 2, consistent with a prior report describing mixed B- and T-immunoblastic proliferation [4]. Other markers, such as ALK1, EBV, and HHV-8 were negative.

These features contrast with intravascular large B-cell lymphoma, which typically shows extensive intravascular involvement, strong expression of B-cell markers such as CD20 and PAX5, light chain restriction, and clonal immunoglobulin rearrangement. CD30, EBV, and HHV8 are usually negative in IVLBCL.

Our findings add to the growing recognition that ILVIP is an incidental, reactive finding identified in gastrointestinal resection specimens in patients with bowel obstruction without systemic symptoms of lymphoma. Immunoblasts in this setting exhibit a postgerminal center B-cell immunophenotype with a high proliferation index and no evidence of clonality, as judged by polytypic expression of kappa and lambda light chains and without clonal immunoglobulin gene rearrangement.

Importantly, erroneous diagnosis of IVLBCL in Patient 2 prompted extensive, ultimately unnecessary evaluation. Therefore, pathologists and clinicians should maintain a high index of suspicion for ILVIP when interpreting findings in specimens with intralymphovascular immunoblastic proliferations, especially when the clinical presentation lacks features of lymphoma.